Cancer is a global problem which affects an estimated 5.9 million people worldwide annually. There are many types of cancer, some of the most common in North America include breast, lung, colon and lymphatic cancer. Although chemotherapy has had positive impact on the survival rate of cancer patients in the last 30 years, most human cancers are, or become resistant to chemotherapy. Thus, there is a tremendous need for anticancer drugs which are more effective and which can act on drug resistant tumors.
Two important features of cancer cells is their ability to proliferate abnormally leading to tumor formation and growth, and to invade other tissues leading to metastases. It is thought that genetic damage to specific genes is responsible for the transformation of cells and the development of cancer in humans. The genetic damage found in human cancer cells can be divided into two types. One of these involves the mutation of oncogenes which results in continuous proto-oncogene activation. The second involves the mutation of tumor suppressor genes which results in the loss of their function. Genetic damage to proto-oncogenes or to tumor suppressor genes leads to oncogene activation in the absence of stimuli and to uncontrolled cellular proliferation. Damage has been found to one or another proto-oncogenes and tumor suppressor genes with some consistency in a variety of human malignancies.
Two oncogenic transcription factors, fos and jun, have been shown to be involved and required for the induction of genes involved in cellular proliferation and in particular, in cellular proliferation in many tumor cell lines. Inhibition of the expression of these two genes leads to the inhibition of cellular proliferation. One of the most life threatening aspects of cancer is the development of metastases. Generally, most solid tumors can be removed surgically from the primary site resulting in a local cure. However, if the cancer cells have invaded vascular channels and metastasized to a different organ, then the likelihood of a complete cure is reduced. Thus, agents which reduce the metastatic properties of cancer cells would be beneficial for the treatment of cancer.
The cellular processes thought to play an important role in metastases include; increased cellular attachment, tumor cell proteolysis of host tissue, tumor cell locomotion and colony formation. These processes occur in a sequential order. First, tumor cells attach to the basement membrane through their surface receptors of integrin and non-integrin types to ligands such as collagen, laminin and fibronectin in the basement membrane. After attachment, a localized zone of lysis of the basement membrane occurs at the point of cell attachment. The tumor cells produce and secrete degradative enzymes, such as collagenase and gelatinase, which degrade the basement membrane and allow the infiltration and locomotion of tumor cells into the host organ. There is a positive association between tumor aggressiveness and the ability of cells to produce a group of enzymes, matrix metalloproteases, involved in the invasive process. Inhibition of certain proteases, such as metalloproteases or serine proteases, have been shown to prevent invasion and metastasis (Alvarez et al. 1990. J. Natl. Cancer Inst. 82: 589-595; Schultz et al 1988, Cancer Res. 48, 5539-5545; and, Wang & Stearns 1988, Cancer Res. 48, 6262-6271). Metalloproteases, such as collagenase have also been associated with cartilage erosion and pathology in arthropathies, such as arthritis.
Ionic vanadium compounds such as vanadyl or vanadate salts in combination with thiosulphate or sulfite compounds have been reported to be useful for treating malignant tumors, arteriosclerosis and mental syndromes in the elderly ((U.S. patent Ser. No. 5,045,316 to Kaplan). Kaplan discloses a daily dose ranging from 0.0043 mg/kg to 0.14 mg/kg of vanadyl or vanadate salts. No mechanism for the action of vanadate and thiosulphate in the disclosed treatments is provided by Kaplan.
In the background of the Kaplan patent it is disclosed that others have reported that vanadium salts have an antineoplastic effect and dietary vanadyl sulphate has been reported to inhibit chemically induced mammary carcinogenesis in rats.
Saxena et al. (Biochem. Pharmacology 45(3): 539-542, 1993) examined the in vivo effects of vanadate on the antioxidant status of control and alloxan diabetic rat livers. Diabetic rats were administered 0.6 mg sodium orthovanadate/ml in drinking water. It should be noted that the present inventor has found that oral administration of orthovanadate to animals at 0.5 mg/ml results in gastric toxicity (See Example 9 herein).
Antioxidants such as .beta.-carotene, n-tocopherol, vitamin E, vitamin C, and glutathione have been reported to have anticancer activity (G. Shklar et al. Nutrition and Cancer, 1993, p.145). It has also been disclosed that a mixture of antioxidants (.beta.-carotene, dl-n-tocopherol acid succinate (vitamin E), vitamin C, and reduced glutathione) was very effective in preventing carcinogenesis in an in vivo cancer model and was more effective than the individual components of the mixture as cancer chemopreventive agents.